The Multifaceted Role of Growth Differentiation Factor 15 (GDF15): A Narrative Review from Cancer Cachexia to Target Therapy

• Published in: Biomedicines Vol. 13; no. 8; p. 1931
• Main Authors: Filippini, Daria Maria, Romaniello, Donatella, Carosi, Francesca, Fabbri, Laura, Carlini, Andrea, Giusti, Raffaele, Di Maio, Massimo, Alfieri, Salvatore, Lauriola, Mattia, Pantaleo, Maria Abbondanza, Arribas, Lorena, Oliva, Marc, Bossi, Paolo, Locati, Laura Deborah
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08.08.2025; MDPI
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Appetite; Biomarkers; Body fat; Body mass index; Cachexia; Cancer; cancer biomarker; Cancer therapies; Chemoresistance; Chemotherapy; chemotherapy resistance; Cytokines; Development and progression; GDF15; GFRAL; Growth; Growth factors; Head & neck cancer; head and neck cancer; Head and neck carcinoma; Health aspects; Immune checkpoint inhibitors; Immune response; Inflammation; Insulin resistance; Kinases; Literature reviews; Liu E; Liu, Timothy; Malignancy; Malnutrition; MAP kinase; Medical prognosis; Metabolism; Metastases; Metastasis; Monoclonal antibodies; Nutrition research; Oxidative stress; Pancreas; Pancreatic cancer; Phenotypes; Physiology; Prognosis; Prostate; Prostate cancer; Proteins; Radioresistance; Review; Smad2 protein; Solid tumors; Squamous cell carcinoma; Stem cells; Therapeutic targets; Tumor necrosis factor-TNF; Italy; chemotherapy resistance; head and neck cancer; cancer biomarker; GDF15; GFRAL; cachexia
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines13081931

Background: Growth Differentiation Factor 15 (GDF15) has emerged as a key biomarker and therapeutic target in oncology, with roles extending beyond cancer cachexia. Elevated GDF15 levels correlate with poor prognosis across several solid tumors, including colorectal, gastric, pancreatic, breast, lung, prostate, and head and neck cancers. GDF15 modulates tumor progression through PI3K/AKT, MAPK/ERK, and SMAD2/3 signaling, thereby promoting epithelial-to-mesenchymal transition, metastasis, immune evasion, and chemoresistance via Nrf2 stabilization and oxidative stress regulation. Methods: We performed a narrative review of the literature focusing on the role of GDF15 in solid tumors, with a particular emphasis on head and neck cancers. Results: In head and neck squamous cell carcinoma (HNSCC), GDF15 overexpression is linked to aggressive phenotypes, radioresistance, poor response to induction chemotherapy, and failure of immune checkpoint inhibitors (ICIs). Similar associations are observed in colorectal, pancreatic, and prostate cancer, where GDF15 contributes to metastasis and therapy resistance. Targeting the GDF15-GFRAL axis appears therapeutically promising: the monoclonal antibody ponsegromab improved cachexia-related outcomes in the PROACC-1 trial, while visugromab combined with nivolumab enhanced immune response in ICI-refractory tumors. Conclusions: Further investigation is warranted to delineate the role of GDF15 across malignancies, refine patient selection, and evaluate combinatorial approaches with existing treatments.